Hemorrhoids are part of the normal human anatomy of the anal canal. In their physiological state they act as cushions composed of arterio-venous channels and connective tissue that aid the passage of stool. They become pathological or piles when swollen or inflamed. Hemorrhoids are classified according to their origin and the dentate line (pectinate line) serves as an anatomic border.
External hemorrhoids are dilations of anorectal vessels below the dentate line, which occur outside the anal verge (the distal end of the anal canal). Specifically, external hemorrhoids are varicosities of the veins draining the territory of the inferior rectal arteries, which are branches of the internal pudendal artery. External hemorrhoids commonly present with pain in the area of anus and often accompanied by swelling and irritation. External hemorrhoids are prone to thrombosis. If the vein ruptures and/or a blood clot develops, the hemorrhoid becomes a thrombosed hemorrhoid.
Internal hemorrhoids are dilations of anorectal vessels above the dentate line, which occur inside the rectum. Specifically, internal hemorrhoids are varicosities of veins draining the territory of branches of the superior rectal arteries. As this area lacks pain receptors, internal hemorrhoids are usually not painful and many people are not aware that they have the condition. However, internal hemorrhoids may bleed when irritated and untreated internal hemorrhoids can lead to two severe forms of hemorrhoids: prolapsed and strangulated hemorrhoids. Prolapsed hemorrhoids are internal hemorrhoids that are so distended that they are pushed outside the anus. If the anal sphincter muscle goes into spasm and traps a prolapsed hemorrhoid outside the anal opening, the supply of blood is cut off, and the hemorrhoid becomes a strangulated hemorrhoid.
Some hemorrhoids are regarded as mixed hemorrhoids (internal-external), arising from the inferior and superior hemorrhoidal plexi and their anastomotic connections, covered by mucosa in the superior part and skin in the inferior part, so they have somatic pain fibers.
Internal hemorrhoids are further classified into four grades according to the extent of prolapse. In first-degree hemorrhoids, the hemorrhoidal tissue protrudes into the lumen of the anal canal, but does not prolapse outside the anal canal. The veins of the anal canal are increased in size and number and may bleed at the time of evacuation. Second-degree hemorrhoids may prolapse beyond the external sphincter and be visible during evacuation but spontaneously return to lie within the anal canal. Third-degree hemorrhoids protrude outside the anal canal and require manual reduction, and fourth-degree hemorrhoids are irreducible and are constantly prolapsed.
A number of factors may lead to the formations of hemorrhoids, which include irregular bowel habits (constipation or diarrhea), exercise, gravity, low-fiber diet, increased intra-abdominal pressure (prolonged straining), pregnancy, obesity, prolonged sitting time, genetics, absence of valves within the hemorrhoidal veins, and aging.
Existing conservative treatments typically include life style modification, such as improving anal hygiene, increasing the intake of dietary fiber and fluids in the diet, and avoiding constipation or diarrhea, sitz baths, and rest; oral medication and topical treatment. In Europe and Asia, oral vasotopic drugs are used for treating hemorrhoids. It has been reported recently that oral micronized, purified flavonoid fraction rapidly relieves hemorrhoidal bleeding.
Many over the counter topical treatment products are available for hemorrhoids, which include pads, topical ointments, creams, gels, lotions, and suppositories. These preparations may contain various ingredients such as local anesthetics, corticosteroids, vasoconstrictors, antiseptics, keratolytics, protectants (such as mineral oils, cocoa butter), astringents (ingredients that cause coagulation, such as witch hazel), and other ingredients. Topical application of corticosteroids may ameliorate local perianal inflammation, however, long term use of high-potency corticosteroid creams can cause permanent damage and thinning of the perianal skin. Local anesthetics, such as 5% lidocaine ointment, decrease permeability to sodium ions in neuronal membranes, resulting in inhibition of depolarization, blocking transmission of nerve impulses. Preparation H®, one of the world's best-selling hemorrhoid treatments, contains 0.25% phenylephrine, a drug which constricts blood vessels. Preparation H may improve local symptoms but does not treat the underlying disorder and long term use is discouraged due to local irritation of the skin. Most of these topical treatment products help the patient maintain personal hygiene, and may alleviate symptoms of pruritus and discomfort. There are no prospective randomized trials suggesting that they reduce bleeding or prolapse.
Several nonsurgical procedures have been used to treat hemorrhoids, which function by ablation, sclerosis, or necrosis of mucosal tissues. These include rubber band ligation, sclerotherapy, and cauterization by using electrocautery, infrared radiation, or cryosurgery. When conservative medical management fails, surgeries have been used to treat severe hemorrhoids, for example, hemorrhoidectomy, doppler guided transanal hemorrhoidal dearterialization, and stapled hemorrhoidectomy. However, all surgical treatments are associated with some degree of complications, including bleeding, infection, anal strictures, and urinary retention due to the close proximity to the rectum of the nerves that supply the bladder.
The macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives thereof, of soil microorganisms belonging to the genus Streptomyces. The avermectin series and milbemycin series of compounds are very potent antiparasitic agents, useful against a broad spectrum of endoparasites and ectoparasites in mammals and also having agricultural utilities against various nematode and insect parasites found in and on crops and in soil. Compounds of this group include avermectins, milbemycins, and their semi-synthetic derivatives, for example, ivermectin, doramectin, emamectin, eprinomectin, selamectin, latidectin, milbemectin, moxidectin, nemadectin, milbemycin oxime, and lepimectin. These chemicals have been described, for example, in U.S. Pat. Nos. 3,950,360, 4,199,569, 4,879,749 and 5,268,710. The avermectins and, to a lesser extent, the milbemycins, have revolutionized antiparasitic and antipest control over the past few decades.
In terms of their mechanism of action as antiparasitic agents, the avermectins block the transmittance of electrical activity in nerves and muscle cells by activating voltage dependent membrane-bound proteins containing chloride channels. Chloride channel blockers in both insects and mammals are highly toxic convulsants causing a hyperexcitation of the nervous system through antagonism of the inhibitory neurotransmitter GABA. Avermectin compounds effectively block GABA stimulated uptake and cause a release of chloride-channel dependent neurotransmitters. Milbemycin compounds have a similar mechanism of action, but a longer half-life than the avermectins. Milbemycin compounds open glutamate sensitive chloride channels in neurons and myocytes of invertebrates, leading to hyperpolarization of these cells and blocking of signal transfer.
Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since mid-1980's. It is commercially available for animal use as Cardomec™ (for felines), Zimecterin® (for equines) and Ivomec® (for bovines) by MERIAL Limited, Duluth, Ga. The medicine is available in tablets, paste, or chewables for heartworm prevention, topical solution for ear mite treatment, or as oral or injectable solution for other parasite problems.
Ivermectin is also commercially available from Merck & Co., Inc for human use as Stromectol® for eradication of threadworm Strongyloides stercoralis, and for eradication of Onchocerca volvulus. The medicine is available in tablets and is orally administered by the patients. Magda et al. (Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653) describe a method of topical application of ivermectin to treat head lice. U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a form of rosacea associated with the ectoparasite Demodex by eliminating mites.
Recently, ivermectin has also been found useful in treating dermatological conditions. U.S. Pat. Nos. 6,133,310, 6,433,006, 6,399,652, 6,399,651 and 6,319,945 (to Parks) disclose methods of treating acne rosacea, seborrheic dermatitis, acne vulgaris, transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions by topically applying an avermectin compound, particularly ivermectin, to the affected areas.
Hemorrhoids are a common public health problem. Symptomatic hemorrhoids affect at least 50% of the American population at some time during their lives, with about 5% of the population suffering at any given time. Moreover, the existing topical medications for treating hemorrhoids have limited effects. Therefore, there is a need for more effective and improved topical compositions and minimal invasive methods for treating hemorrhoids.